Faculty Collaboration Database

Contribution of independent and pleiotropic genetic effects in the metabolic syndrome in a hypertensive rat. PLoS One 2017;12(8):e0182650

Date

08/10/2017

Pubmed ID

28792545

Pubmed Central ID

PMC5549746

DOI

10.1371/journal.pone.0182650

Scopus ID

2-s2.0-85027186892 (requires institutional sign-in at Scopus site)   7 Citations

Abstract

Hypertension is a major risk factor for cardiovascular disease, Type 2 diabetes, and end organ failure, and is often found concomitant with disorders characteristic of the Metabolic Syndrome (MetS), including obesity, dyslipidemia, and insulin resistance. While the associated features often occur together, the pathway(s) or mechanism(s) linking hypertension in MetS are not well understood. Previous work determined that genetic variation on rat chromosome 17 (RNO17) contributes to several MetS-defining traits (including hypertension, obesity, and dyslipidemia) in the Lyon Hypertensive (LH) rat, a genetically determined MetS model. We hypothesized that at least some of the traits on RNO17 are controlled by a single gene with pleiotropic effects. To address this hypothesis, consomic and congenic strains were developed, whereby a defined fragment of RNO17 from the LH rat was substituted with the control Lyon Normotensive (LN) rat, and MetS phenotypes were measured in the resultant progeny. Compared to LH rats, LH-17LN consomic rats have significantly reduced body weight, blood pressure, and lipid profiles. A congenic strain (LH-17LNc), with a substituted fragment at the distal end of RNO17 (17q12.3; 74-97 Mb; rn4 assembly), showed differences from the LH rat in blood pressure and serum total cholesterol and triglycerides. Interestingly, there was no difference in body weight between the LH-17LNc and the parental LH rat. These data indicate that blood pressure and serum lipids are regulated by a gene(s) in the distal congenic interval, and could be due to pleiotropy. The data also indicate that body weight is not determined by the same gene(s) at this locus. Interestingly, only two small haplotypes spanning a total of approximately 0.5 Mb differ between the LH and LN genomes in the congenic interval. Genes in these haplotypes are strong candidate genes for causing dyslipidemia in the LH rat. Overall, MetS, even in a simplified genetic model such as the LH-17LN rat, is likely due to both independent and pleiotropic gene effects.

Author List

Ma MCJ, Pettus JM, Jakoubek JA, Traxler MG, Clark KC, Mennie AK, Kwitek AE

Authors

Karen C. Clark Research Scientist I in the Physiology department at Medical College of Wisconsin
Anne E. Kwitek PhD Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blood Pressure
Disease Models, Animal
Genetic Loci
Genetic Pleiotropy
Genetic Predisposition to Disease
Haplotypes
Kidney
Lipid Metabolism
Liver
Male
Metabolic Syndrome
Models, Genetic
Phenotype
Polymorphism, Single Nucleotide
RNA, Messenger
Rats, Inbred SHR
Real-Time Polymerase Chain Reaction
Species Specificity